In-Depth Validation of Closed-Vial Technology

Continuous improvement in the development of technologies for aseptic filling of injectable products has led to innovative solutions. The main driver for innovation is that a small deviation from GMP may trigger product contamination leading to septic shock and even death for the patient. For example, analysis of an outbreak database has shown that, among 1537 patients contaminated by parenteral products, the mortality rate reached 15%. Of those contaminations, 20% were due to deviations during pharmaceutical drug manufacturing, showing that improvement of injectable processing operations is worth investigating (1).

The rate of contamination has been strongly reduced during the past 50 years thanks to major innovations targeting both the container and the filling technologies. Among the major changes observed during this period were:

Emergence of the vial as the standard primary packaging, replacing the ampul. This change resulted in a significant decrease in breakage, a reduction in risk of contamination through small cracks, and elimination of glass particle generation when the ampul is opened.

Development of prefilled syringes and cartridges to ease drug administration by healthcare practitioners or patients.

Adoption of new materials such as cyclo-olefin co-polymer (COC) and cyclo-olefin polymer (COP) that increase resistance to damage and eliminate glass particles.

Creation of a physical barrier between the operator and the filling area. Initially, barriers were simple walls, but now can be isolators that prevent the operator from coming in direct contact with the product, the container, and the product contact parts.

Use of extensive in-process control (IPC) and process analytical technology (PAT) to perform on-line checks and to monitor the process itself. On top of the classical weight check, new checks such as continuous environmental monitoring, equipment performance monitoring, automatic particle inspection, and leak detection are now frequently used to reject defective containers and batches.

Crystal closed-vial technology aims to further address the quality issue for the patient and also to simplify the aseptic filling process (2, 3). The concept of crystal closed-vial technology consists of three different steps:

The vial is molded and directly assembled with its stopper in a ISO5 clean room, leading to a clean and closed vial.

The vial is then sterilized by gamma irradiation, leading to a clean, sterile, ready-to-fill vial.

During the filling process, a needle punctures the stopper and dispenses the liquid, followed by immediate laser resealing of the stopper to restore closure integrity and capping by snap fit. These three operations are performed in an ISO5 environment.

Although the goal is still to fill a vial with the pharmaceutical drug under aseptic conditions, closed-vial technology allows for some differences. Three main advantages include:

Increased safety for the patient: the vial remains closed during the process, significantly reducing the risk of a contaminant entering the vial compared with other containers remaining fully open, resulting in a two-log reduction of contamination risk due to exposure (4).

Simplification of the filling process: the vial is delivered clean and sterile, allowing the pharmaceutical manufacturer to eliminate the preparation of the container components (i.e., washing, siliconization, and depyrogenization for classical glass vials).

Easier handling for healthcare professionals: the handling, the opening, the piercing of the stopper, and collection of the product are facilitated compared with glass vials, because of the special shape of the stopper without a recess area. Out of 246 hospital professionals, 87% preferred closed-vial containers versus 6% who preferred glass-vial containers, according to a survey of practitioners and nurses conducted in Europe and the US (5).

Eliminating some process technologies requires the introduction of other solutions, such as:

Use of COC and thermoplastic elastomer (TPE) as container material for the vial body and for the stopper, respectively

Filling with a special needle piercing the stopper

Laser resealing of the piercing trace to restore closure integrity

Capping by snap fit of high-density polyethylene caps.

Making such changes raises several questions from the pharmaceutical industry regarding their acceptance by regulatory authorities. To ensure that the technology is suitable for aseptic filing of injectables, a series of tests should be performed regarding container materials and characteristics, container manufacturing process, and filling process.

This article describes the major changes that have been introduced, the validation processes, and their results. These data have been used by GSK Biologicals to support the approval for Europe of Synflorix, a vaccine against pneumococcal infection, using the closed vial for a Type II variation of the previous approval of the same product in other containers. It is clear that product stability data are mandatory to obtain regulatory product approval, but providing a complete set of supporting data can help the applicant to set up a complete and consistent file for submission to the authorities.